Multiple Regression Analysis of Pharmacogenetic Variability of Carvedilol Disposition in 54 Healthy Japanese Volunteers

Abstract

Carvedilol is a b-adrenoceptor antagonist used clinically to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias.1-4) Carvedilol is highly lipophilic and eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose.5) The drug is absorbed rapidly from the gastrointestinal tract after oral administration; however, the amount of unchanged drug excreted in the feces was 23% of the administered dose probably because of incomplete intestinal absorption.6) In addition, orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low bblocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.6) The mean absolute bioavailability of R-and S-enantiomer in humans is 31% and 15%, respectively. 7)In the previous study, we investigated the effect of genetic polymorphisms of cytochrome P450 (CYP) 2D6 on the pharmacokinetics of R-and S-carvedilol in 23 healthy Japanese volunteers.8) The large interindividual variability was observed in the pharmacokinetics of carvedilol, and the coefficient of variation of the weight (WT)-corrected oral clearance ((CL/F)/ WT) value among the subjects was 36.1%. In addition, the (CL/F)/WT value was highly correlated with the apparent distribution volume ((V/F)/WT) value among the subjects, suggesting that the interindividual difference in bioavailability (F) was at least partly responsible for the pharmacokinetic variability of carvedilol. The (CL/F)/WT and (V/F)/WT values of R-and S-carvedilol were significantly lower in healthy volunteers with at least one CYP2D6*10 allele than those with the CYP2D6*1/*1 and *1/*2 genotype. The result suggested that the systemic and/or pre-systemic metabolism of R-and S-carvedilol in the liver is significantly decreased in Japanese subjects with the CYP2D6*10 allele.Carvedilol is metabolized extensively via aliphatic sidechain oxidation and conjugation pathways, as well as the aromatic ring oxidation pathway which is mediated mainly by CYP2D6. 6) Oldham et al. reported that considerable metabolic activity for carvedilol is observed in CYP1A2, 2C9, 2D6, and 3A4. 9) On the other hand, it is still unclear whether the other P450s are involved in the metabolism of carvedilol. However, a substrate of CYP2C9, such as phenytoin, is partly catalyzed by another CYP2C subfamily, CYP2C19. 10)CYP3A5 is another important CYP3A protein in the liver, the substrate specificity of which largely overlaps with that of CYP3A4.11) In addition, Ohno et al. reported that UDP-glucuronosyltransferase (UGT) 1A1, 2B4, and 2B7 as well as human hepatic microsomes are capable of catalyzing the glucuronidation of carvedilol.12) Moreover, carvedilol has high affinity for the multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp). Giessmann et al. reported that the intestinal expression of P-gp is a major variable in the disposition of carvedilol. 13)In the presen...

Inhibitory and Stimulative Effects of Amiodarone on Metabolism of Carvedilol in Human Liver Microsomes

“…[13][14][15] Assay of Carvedilol Enantiomers The amount of carvedilol in the samples was measured using chiral high performance liquid chromatography (HPLC) as described by Saito et al with minor modifications. [7][8][9][10]16) Briefly, carvedilol was extracted from the samples (0.1 ml) with 5 ml diethylether after alkalization in 3 ml of 0.1 M Britton-Robinson buffer (pH 8.5). The organic phase was transferred and evaporated dry in a water bath at 45°C.…”

“…6) In addition, our previous findings indicated that R-carvedilol is metabolized mainly by CYP2D6 and partly by CYP1A2, 2C9, and 3A4, and that S-carvedilol is metabolized mainly by CYP1A2 and partly by CYP2C9, 2D6, and 3A4. [7][8][9][10] On the other hand, Ohno et al found that uridine 5Ј-diphosphate (UDP)-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol using microsomes from insect cells expressing human UGT. 11) In addition, they have demonstrated that glucuronidation of R-carvedilol is mediated by UGT1A1 and 2B4, and that glucuronidation of S-carvedilol is mediated by UGT2B7 and 2B4.…”

Involvement of the CYP1A Subfamily in Stereoselective Metabolism of Carvedilol in .BETA.-Naphthoflavone-Treated Caco-2 Cells

“…[3][4][5] Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways.6) Oldham and Clarke reported that oxidative activity of carvedilol is observed in cytochrome P450 (CYP) 2D6, 1A2, 3A4, and 2C9.7) In addition, Ohno et al reported that UDPglucuronosyltransferase (UGT) 2B7, 1A1, and 2B4 are capable of catalyzing the glucuronidation of carvedilol.8) However, it has been unknown whether the intestine also plays a role in the first-pass presystemic metabolism of carvedilol, although several CYP and UGT isoforms are expressed in human intestinal epithelial cells. 9,10) We previously investigated the metabolism of carvedilol in human intestinal epithelial Caco-2 cells.…”

“…[3][4][5] Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways.…”

Stereoselective Metabolism of Carvedilol by the .BETA.-Naphthoflavone-Inducible Enzyme in Human Intestinal Epithelial Caco-2 Cells

“…Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the blood concentration of R-enantiomer with very low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity. 5,6) Both enantiomers are eliminated predominantly by hepatic metabolism, with renal excretion accounting for only 0.3% of the administered dose. 7) Carvedilol is metabolized extensively via aliphatic side-chain oxidation, aromatic ring oxidation, and conjugation pathways.…”